Alzheimer's disease (AD) is the most common form of neurodegeneration however, adequate therapies do not exist to prevent or treat AD. Since 1999, Abeta immunotherapy has been shown to lower cerebral Abeta levels and improve cognition in AD mouse models. Unfortunately, a Phase II clinical trial of active immunization using full-length human Abeta peptide was halted in 2002 due to the onset of meningoencephalitis in ~6% of AD patients. T cell recognition of the full-length Abeta peptide may have induced an autoimmune response. A new clinical trial is underway to test the safety of passive immunization by monthly intravenous injections of humanized Abeta monoclonal antibodies. However, an urgent need remains for a long-lasting, safe and effective active Abeta vaccine that would be more readily available to a larger population of patients. In the first 4.5 years of this RO1, we focused on optimization of mucosal Abeta immunization in wild-type mice and AD mouse models. In this competitive renewal, our goals are to generate a safe and effective active Abeta vaccine and, to define the roles of complement and complement receptors in Abeta clearance and vaccine-related adverse events. First, we hypothesize that Abeta immunotherapy will be made safer by avoiding an Abeta-specific cellular immune response. In Aim 1, we will test novel short Abeta immunogens that target Abeta B cell epitopes while avoiding Abeta-specific T cell epitopes using 3 routes of administration (intranasal, subcutaneous, and transcutaneous) in WT mice. Humoral and cellular immune responses will be characterized. In Aim 2, the best short Abeta immunogens/routes will be tested in young (prevention) and old (therapeutic) J20 APP tg mice and compared with full-length Abeta immunization using our new combined adjuvants CpG/LT(R192G) that induced T cell proliferation into brains of AR40/42 immunized mice. Immune responses, as well as biochemical and neuropathological, and behavioral changes will be examined. Immunologic memory will be tested. Second, we hypothesize that complement and complement receptors are important for removal of Abeta and immune complexes, and may play a role in the safety of such a vaccine. In Aim 3, we will determine the roles of complement C3 and complement receptor CR3 (Mac-1, CD11b/CD18) in Abeta clearance, AD-like pathology, and vaccine-related adverse events including microhemorrhage. We have generated APP tg mice lacking C3 and will generate APP tg mice lacking Mac-1. These mice will be compared to J20 APP mice for AD-like pathology and response to active and passive Abeta immunization. Lay Summary: Abeta immunotherapy has the potential to prevent and treat Alzheimer's disease but must be made safer. We are working towards a safer active Abeta vaccine and exploring mechanisms involving complement and its receptors.